Tertiary Lymphoid Structures in Cancer: Drivers of Antitumor Immunity, Immunosuppression, or Bystander Sentinels in Disease?

Abstract

Secondary lymphoid organs are integral to initiation and execution of adaptive immune responses. These organs provide a setting for interactions between antigen-specific lymphocytes and antigen-presenting cells recruited from local infected or inflamed tissues. Secondary lymphoid organs develop as a part of a genetically preprogrammed process during embryogenesis. However, organogenesis of secondary lymphoid tissues can also be recapitulated in adulthood during de novo lymphoid neogenesis of tertiary lymphoid structures (TLSs). These ectopic lymphoid-like structures form in the inflamed tissues afflicted by various pathological conditions, including cancer, autoimmunity, infection, or allograft rejection. Studies are beginning to shed light on the function of such structures in different disease settings, raising important questions regarding their contribution to progression or resolution of disease. Data show an association between the tumor-associated TLSs and a favorable prognosis in various types of human cancer, attracting the speculation that TLSs support effective local antitumor immune responses. However, definitive evidence for the role for TLSs in fostering immune responses in vivo are lacking, with current data remaining largely correlative by nature. In fact, some more recent studies have even demonstrated an immunosuppressive, tumor-promoting role for cancer-associated TLSs. In this review, we will discuss what is known about the development of cancer-associated TLSs and the current understanding of their potential role in the antitumor immune response.

Role of chemokines in ectopic lymphoid structures formation in autoimmunity and cancer

“…The crucial importance of HEVs has been confirmed in multiple studies, in which the presence of this peculiar ELS‐associated vasculature structure correlates with better survival rates and decreased incidence of metastasis …”

“…Alongside with chemokines, also LTs are critically important for TLO neogenesis, both in cancer and chronically inflamed tissues …”

“…Over the last decade, a huge effort has been made to identify and potentially manipulate for therapeutic purposes the mechanisms controlling the ELN in cancer …”

“…For example, studies in lung carcinoma have confirmed that CXCL13 is produced by FDCs located in the GC‐like zone and constitutes the chemotactic signal for CXCR5 + Tfh, which can be detected in the same area of FDCs. CCL21, instead, is predominantly produced in the lymphatic vessels . Overall, a more favorable outcome has been observed in patients with solid cancers, for example, breast cancer, colorectal carcinomam, melanoma, and non‐small cell lung cancer characterized by the presence of ELS within the neoplastic tissue …”

Prognostic relevance of tertiary lymphoid organs following neoadjuvant chemoradiotherapy in pancreatic ductal adenocarcinoma

“…During chronic inflammatory reactions, lymphocytes can accumulate and lead to the de novo formation of B cell follicles and T cell areas . This phenomenon has been termed “tertiary lymphoid neogenesis” or “TLO formation.” Despite the presence of structural differences between SLOs and TLO, various mechanisms that control the initial development, cellular composition and functional maintenance of these structures are shared …”